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GLYCOPEPTIDE ANTIBIOTICS from Old Mississipi mud … … to new derivatives : a critical appraisal

GLYCOPEPTIDE ANTIBIOTICS from Old Mississipi mud … … to new derivatives : a critical appraisal. F. Van Bambeke & P.M. Tulkens Pharmacologie cellulaire et moléculaire Université catholique de Louvain – Brussels - Belgium.

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GLYCOPEPTIDE ANTIBIOTICS from Old Mississipi mud … … to new derivatives : a critical appraisal

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  1. GLYCOPEPTIDE ANTIBIOTICSfrom Old Mississipi mud …… to new derivatives:a critical appraisal F. Van Bambeke & P.M. Tulkens Pharmacologie cellulaire et moléculaire Université catholique de Louvain – Brussels - Belgium Presented at the 5th European Congress of Chemotherapy, Rhodes, Greece, 17-20 October 2003

  2. Glycopeptide story: from natural to semi-synthetic derivatives ~ 1950 : discovery of vancomycin in Mississipi mud ~ 1985 : large clinical use in USA Gram(+) infections and digestive tract decontamination • Problem: • toxicity of vancomycin due to impurities  better purification procedures • ~ 1980 : • discovery of teicoplanin, as a natural GP with improved PK • largely used in Europe

  3. vancomycin teicoplanin (1996) oritavancin dalbavancin (1999) (2003) phase II / III Glycopeptide story: from natural to semi-synthetic derivatives ~ 1990 : Launching of large scale research program for finding GP with optimized properties  hemi-synthetic compounds Malabarba and Nicas Med Res Rev. (1997)17:69-137;Curr Med Chem. (2001) 8:1759-7

  4. Peptidoglycan synthesis reticulation cell wall D-ala cytosol precursor synthesis

  5. binding to D-Ala-D-ala prevents the reticulation of peptidoglycan precursors Glycopeptide mechanism of action

  6. But resistance came in ...

  7. large clinical use in USA started in ~ 1985 Resistance in enterococci Bonten et al, Lancet ID (2001) 1:314-325

  8. Resistance in enterococci  glycopeptide binding to depsipeptide D-Lac, D-Ser P. Courvalin et al’s work

  9. 1 hydrogen bound is missing ! Resistance in enterococci from susceptible … … to resistant Arthur et al, Trends Microbiol (1996) 4:401-407

  10. Resistance in enterococci  glycopeptide binding to depsipeptide D-Lac, D-Ser

  11. AB MIC AMP VAN GEN RIF LVX TET SMX Q-D LZD 64 8 128 2048 8 128 0.125 0.5 2 Resistance in staphylococci (GISA)

  12. Resistance in staphylococci (GISA) tickened Cell wall multiplication of the target ! Cui et al J Clin Microbiol (2003) 41:5-14 Hiramatsu Lancet ID (2001) 1:147-155

  13. AB MIC VAN TEC 32 4 Resistance in staphylococci (GRSA)

  14. Gram (+) & MRSA, GISA, VRE quickly, conc. dependent bactericidal t ½  diffusibility (CNS) AUC/MIC & Cmax/MIC  side effects  Glycopeptides: what can we improve ? parameter vanco - teico ideal glycopeptide spectrum Gram (+) & MRSA but VRE - GISA PD static or slowly bactericidal PK t ½ short for vanco PK/PD high doses to reach appropriate AUC/MIC & Cmax/MIC safety (red-man syndrome) oto-& nephrotoxicity

  15. Glycopeptide updated mechanism of action dimerization and / or membrane anchoring  activity

  16. Glycopeptide updated mechanism of action in VRE efficient binding still possible !

  17. H O H O O H O O O C H 3 H N 2 O C l H O H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H Glycopeptides: how can we improve ?

  18. H O H O O H O O O C H 3 H N 2 O C l H O H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H Glycopeptides: how can we improve ? binding to D-Ala-D-Ala

  19. H O H O O H O O O C H 3 H N 2 O C l H O H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H Glycopeptides: how can we improve ? dimerization binding to D-Ala-D-Ala

  20. H O H O O H O O O C H 3 H N 2 O C l H O H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H Glycopeptides: how can we improve ? membrane anchoring, transglycosylase inhibition dimerization binding to D-Ala-D-Ala

  21. Molecules in clinical development:DESIGN

  22. H O H O O H O O O C H 3 H N 2 O C l H O H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H From vancomycin to oritavancin

  23. H O H O O H O O O C H 3 H N 2 O C l H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H From vancomycin to oritavancin epi-vancosamine O H

  24. H N 2 H O H C O 3 C H 3 From vancomycin to oritavancin H O H O • 4‑epi-vancosamine • self-association capacity O H O O O C H 3 H N 2 O C l O H H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H LY264626

  25. C l H N 2 H O H C O 3 C H 3 From vancomycin to oritavancin • lipophilic side chain • activity including against resistant enterococci H O H O O H O O O C H 3 H N O C l O H H C O O 3 H O C l O O O H H N N N N N H H H H N O O N H C H 3 O C O N H 2 H O O C O H H O O H

  26. From teicoplanin to dalbavancin C O H N H O H O O C l O H O O O O H O H O O H O C l O N H A c O O H H N H O N N 2 N N N H H H H N O O H O O C H O O O H O H H O O O H O O H O H O H

  27. From teicoplanin to dalbavancin C O H N H O H O O O H O O O O H O H O O H O C l O N H A c O O H H N HCH O N N 3 N N N H H H H N O O C l H O O C H O O O H O H H O O O H O O H O H O H

  28. From teicoplanin to dalbavancin C O H N • removal of • N-acetylglucosamine • activity (against resistant enterococci) H O H O O O H O O O HO C l O O O H H N HCH O N N 3 N N N H H H H N O O C l H O O C H O O O H O H H O O O H O O H A40926 O H O H

  29. N N H- From teicoplanin to dalbavancin C O H N H O H O O O H O O O HO C l • activity O O O H H N HCH O N N 3 N N N H H H H N O O C l O C H O O O H O H H O O O H O O H O H O H O H

  30. Molecules in clinical development:IN VITRO DATAmicrobiologypharmacodynamics

  31. Spectrum of activity Most of data from Candiani, et al. (1999) JAC 44: 179-92

  32. Pharmacodynamic properties of oritavancin conc. dependent, bactericidal effect static effect Allen & Nicas, FEMS Microbiology Rev (2003) 26:511-532

  33. control 0.25 µg/ml 300 2.5 µg/ml 50 µg/ml 200 10 µg/ml Cellular accumulation 100 25 µg/ml 0 ORI VAN PK/PD properties of oritavancinin a model of S.aureus infected macrophages VAN ORI 107 105 CFU/mg prot 103 101 0 5 10 15 20 25 Time (h) Seral et al AAC (2003) 47 : 2283-2292

  34. Molecules in clinical development:IN VIVO DATApharmacokineticspharmacodynamics

  35. once-a-day administration once-a-week administration Pharmacokinetic properties Intermune, Inc, data on file Steiert & Schmitz, Curr.Opin.Investig.Drugs (2002) 3:229-233

  36. MIC of target bugs : MRSA VISA VRE 0.5-4 8 >128 0.13-4 1-8 0.06-1 0.13-8 8-32 64->128 0.06-1 2 0.5->128 PK/PD profile PK/PD breakpoints :

  37. but more patients are needed … Safety profile preclinical studies preliminary data from Phase I and Phase II oritavancin and dalbavancin well tolerated

  38. Molecules in clinical development:IN VIVO DATAclinical studies

  39. Clinical experience complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II/III; double blind, randomized) 517 pts Vancomycin 15 mg/kg bid 3-7days followed by oral cephalexin 10-14 days Oritavancin 1.5-3 mg/kg qd 3-7 days SUCCESS : bacteriological clinical with MRSA 76 % 80 % 80 % 74 % 76 % 74 % = Wasilewski et al 41st ICAAC (2001)

  40. Clinical experience complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II; controlled, randomized) 42 pts Vancomycin, ceftriaxone, cefazolin or clindamycin for 7-21 days Dalbavancin 15 mg/kg day 1 + 7.5 mg/kg day 8 SUCCESS : bacteriological clinical 64 % 76 % 73 % 94 % Selzer et al 13th ECCMID (2003)

  41. In which indications could they be useful ? • which organisms ? • MRSA certainly YES • VRE oritavancin only • VISA limited activity, • … but synergy for dalba + -lactam • S. pneumo other alternatives • which organs ? • severe skin and soft tissues • septicemia / deep organs • endocarditis (combination ?) • CNS infections (penetration ?) clinical experience still lacking

  42. Research is still active … TD-6424

  43. Research is still active … • TD-6424 • in vitro data: MIC MRSA 1 µg/ml MIC VISA 4 µg/ml • antibacterial activity: bactericidal inhibitor of lipid synthesis • activity in animal models endocarditis subcutaneous infections • Phase I studies t ½ ~ 8 h  once-a-day

  44. … but how strong will they be ? We are looking forward these new antibiotics …

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